Type A γ-aminobutyric acid receptors (GABA_ARs) are the principal mediators of inhibitory neurotransmission in the human brain. Endogenous neurosteroids interact with GABA_ARs to regulate acute and chronic anxiety and are potent sedative, analgesic, anticonvulsant and anesthetic agents. Their mode of binding and mechanism of receptor potentiation, however, remain unknown. Here we report crystal structures of a chimeric GABA_AR construct in apo and pregnanolone-bound states. The neurosteroid-binding site is mechanically coupled to the helices lining the ion channel pore and modulates the desensitization-gate conformation. We demonstrate that the equivalent site is responsible for physiological, heteromeric GABA_AR potentiation and explain the contrasting modulatory properties of 3a versus 3b neurosteroid epimers. These results illustrate how peripheral lipid ligands can regulate the desensitization gate of GABA_ARs, a process of broad relevance to pentameric ligand-gated ion channels.

中文翻译：

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神经甾体增强GABA _A受体的结构基础

A型γ-氨基丁酸受体（GABA _A Rs）是人脑中抑制性神经传递的主要介质。内源性神经类固醇与GABA _A Rs相互作用以调节急性和慢性焦虑，并且是有效的镇静剂，镇痛药，抗惊厥药和麻醉药。然而，它们的结合方式和受体增强机制尚不清楚。在这里，我们报告载脂蛋白和孕烯醇酮结合状态的嵌合GABA _A R构造的晶体结构。神经类固醇结合位点与离子通道孔内衬的螺旋机械耦合，并调节脱敏门构象。我们证明等效位点负责生理性，异聚GABA _AR增强，并解释了3a与3b神经甾体差向异构体的相反调节特性。这些结果说明外围脂质配体如何调节GABA _A Rs的脱敏门，这是与五聚体配体门控离子通道广泛相关的过程。